Journal article
Discovery of Aminoglycoside Mimetics by NMR-Based Screening of Escherichia coli A-site RNA
Journal of the American Chemical Society, Vol.125(15), pp.4444-4450
04/16/2003
DOI: 10.1021/ja021354o
PMID: 12683814
Abstract
A method is described for the NMR-based screening for the discovery of aminoglycoside mimetics that bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit high nephrotoxicity and ototoxicity, and their overuse has led to the development of resistance to important microbial pathogens. To identify a new series of aminoglycoside mimetics that could potentially overcome the problems associated with toxicities and resistance development observed with the aminoglycosides, we have prepared large quantities of E. coli 16 S A-site RNA and conducted an NMR-based screening of our compound library in search for small-molecule RNA binders against this RNA target. From these studies, several classes of compounds were identified as initial hits with binding affinities in the range of 70 μM to 3 mM. Lead optimization through synthetic modifications of these initial hits led to the discovery of several small-molecule aminoglycoside mimetics that are structurally very different from the known aminoglycosides. Structural models of the A-site RNA/ligand complexes were prepared and compared to the three-dimensional structures of the RNA/aminoglycoside complexes.
Details
- Title: Subtitle
- Discovery of Aminoglycoside Mimetics by NMR-Based Screening of Escherichia coli A-site RNA
- Creators
- Liping YU - Discovery LaboratoriesThorsten K. Oost - Discovery LaboratoriesJeffrey M. Schkeryantz - Discovery LaboratoriesJianguo Yang - Discovery LaboratoriesDave Janowick - Discovery LaboratoriesStephen W. Fesik - Discovery Laboratories
- Resource Type
- Journal article
- Publication Details
- Journal of the American Chemical Society, Vol.125(15), pp.4444-4450
- Publisher
- American Chemical Society
- DOI
- 10.1021/ja021354o
- PMID
- 12683814
- ISSN
- 0002-7863
- eISSN
- 1520-5126
- Language
- English
- Date published
- 04/16/2003
- Academic Unit
- Biochemistry and Molecular Biology; Medicine Administration
- Record Identifier
- 9984627347702771
Metrics
4 Record Views